Lung cancer is now considered to be the leading cause of cancer death in both men women in the U.S, and despite recent advances in understanding several aspects of the biology of lung cancer, overall patient survival has not improved over the past decade. The aim of this project is to study the ability of a monoclonal antibody (Mb), RS7-3G11, raised against non-small cell carcinoma of the lung (NSCCL), to target and act as a radioimmunotherapeutic agent for the therapy of NSCCL. Our long range goals are to use this MAb in disclosing and treating NSCCL, specifically small metastatic lesions, and as adjuvant therapy to ensure killing of residual viable tumor after surgical debulking or for shrinking tumor prior to surgery. MAb RS7-3G11 has been selected from the panel of MAbs that we have generated against NSCCL for further study due to a number of promising characteristics. Our preliminary results indicate that this MAbs demonstrates: a) a high frequency of antigen expression on a wide variety of tumor types, especially lung, breast, ovarian, cervical, and prostate cancers, with limited expression on normal human tissue; b) the ability to localize to tumor in an animal model; c) the ability to provide reduction in tumor burden in vivo when conjugated to 131I; and d) the ability to internalize into antigen-bearing cells. In view of these observations we feel RS7-3G11 has potential for application in the diagnosis and therapy of non-small cell carcinoma of the lung, as well as possibly carcinomas of the breast, ovary, cervix, and prostate. In order to evaluate RS7-3G11's targeting capability, we will perform a pilot Phase I clinical trial that will test the targeting ability of RS7-3G11 using 99mTc-labeled Fab' fragments in patients with confirmed lung cancer; and if a majority of the known lesions are targeted, the patient will be eligible to enter a Phase I radioimmunotherapy (RAIT) trial utilizing 131I-RS7-3g11 F(ab')2. These studies will provide data regarding tumor targeting sensitivity and resolution of detection, organ distribution and dosimetry, pharmacokinetics, and toxicity of RS7-3G11. In addition, plasma will be studied by immunoassays for HAMA and RS7-3G11-reactive antigen, and characterized by HPLC for stability of labeled antibody in the circulation and presence of high-molecular weight complexes with antigen or HAMA. If successful targeting is achieved, more advanced trials can be designed.